Severe neonatal hypotonia due to <scp><i>SLC30A5</i></scp> variant affecting function of <scp>ZnT5</scp> zinc transporter

The tightly-regulated spatial and temporal distribution of zinc ion concentrations within cellular compartments is controlled by two groups of Zn²⁺ transporters: the 14-member ZIP/SLC39 family, facilitating Zn²⁺ influx into the cytoplasm from the extracellular space or intracellular organelles; and the 10-member ZnT/SLC30 family, mobilizing Zn²⁺ in the opposite direction. Genetic aberrations in most zinc transporters cause human syndromes. Notably, previous studies demonstrated osteopenia and male-specific cardiac death in mice lacking the ZnT5/<i>SLC30A5</i> zinc transporter, and suggested association of two homozygous frameshift <i>SLC30A5</i> variants with perinatal mortality in humans, due to hydrops fetalis and hypertrophic cardiomyopathy. We set out to decipher the molecular basis of a severe hypotonia syndrome. Combining homozygosity mapping and exome sequencing studies of consanguineous Bedouin kindred, as well as transfection experiments and zinc monitoring in HEK293 cells, we demonstrate that a bi-allelic in-frame 3bp deletion variant in <i>SLC30A5</i>, deleting isoleucine within the highly conserved cation efflux domain of the encoded ZnT5, results in lower cytosolic zinc concentrations, causing a syndrome of severe non-progressive neonatal axial and limb hypotonia with high-arched palate and respiratory failure. There was no evidence of hydrops fetalis, cardiomyopathy or multi-organ involvement. Affected infants required nasogastric tube or gastrostomy feeding, suffered from various degrees of respiratory compromise and failure to thrive and died in infancy. Thus, a biallelic variant in <i>SLC30A5</i> (ZnT5), affecting cytosolic zinc concentrations, causes a severe hypotonia syndrome with respiratory insufficiency and failure to thrive, lethal by 1 year of age.